The Epigenetics Revolution (14 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
Emma Whitelaw tested a number of epigenetic proteins in her system, and found that only a few of them caused the increased variation in body weight. One of the proteins that had this effect was Dnmt3a. This is one of the enzymes that transfers methyl groups to DNA, to switch genes off. The other epigenetic protein that caused increased variability in body weight was called Trim28. Trim28 forms a complex with a number of other epigenetic proteins which together add specific modifications to histones. These modifications down-regulate expression of genes near the modified histones and are known as repressive histone modifications or marks. Regions of the genome that have lots of repressive marks on their histones tend to become methylated on their DNA, so the Trim28 may be important for creating the right environment for DNA methylation.
These experiments suggested that certain epigenetic proteins act as a kind of dampening field. ‘Naked’ DNA is rather prone to being switched on somewhat randomly, and the overall effect is like having a lot of background chatter in our cells. This is called transcriptional noise. The epigenetic proteins act to turn down the volume of this random chat. They do this by covering the histones with modifications that reduce the genes’ expression. It’s likely that different epigenetic proteins are important for suppressing different genes in some tissues rather than in others.
It’s clear that this suppression isn’t total. If it were, then all inbred mice would be identical in every aspect of their phenotype and we know this isn’t the case. There is variation in body weight even in the inbred strains, it’s just that there’s even more variation in the mice with the depressed levels of the epigenetic proteins.
This sophisticated balancing act, in which epigenetic proteins dampen down transcriptional noise but don’t entirely repress gene expression, is a cellular compromise. It leaves cells with enough flexibility of gene expression to be able to respond to new signals – be these hormones or nutrients, pollutants or sunlight – but without the genes being constantly ready to fire up just for the heck of it. Epigenetics allows cells to perform the difficult compromise between becoming (and remaining) different cell types with a variety of functions, and not being so locked into a single pattern of gene expression that they become incapable of responding to changes in their environment.
Something that is becoming increasingly clear is that early development is a key period when this control of transcriptional noise first becomes established. After all, very little of the variation in body weight in the original inbred strains could be attributed to the post-natal environment (just 20–30 per cent). Interest is increasing all the time in the role of a phenomenon called developmental programming, whereby events during foetal development can impact on the whole of adult life, and it is increasingly recognised that epigenetic mechanisms are what underlie a major proportion of this programming.
Such a model is entirely consistent with Emma Whitelaw’s work on the effects of decreased levels of Dnmt3a or Trim28 in her mouse studies. The body weight effects were apparent when the mice were just three weeks old. This model is also consistent with the fact that decreased levels of Dnmt3a resulted in the increased variability in body weight, but decreased levels of the related enzyme Dnmt1 had no effect in Emma Whitelaw’s experiments. Dnmt3a can add methyl groups to totally unmethylated DNA regions, which means it is responsible for establishing the correct DNA methylation patterns in cells. Dnmt1 is the protein that maintains pre-established methylation patterns on DNA. It seems that the most important feature for dampening down gene expression variability (at least as far as body weight is concerned) is establishing the correct DNA methylation patterns in the first place.
The Dutch Hunger Winter
Scientists and policy-makers have recognised for many years the importance of good maternal health and nutrition during pregnancy, to increase the chances that babies will be born at a healthy weight and so be more likely to thrive physically. In more recent years, it’s become increasingly clear that if a mother is malnourished during pregnancy, her child may be at increased risk of ill-health, not just during the immediate post-birth infancy, but for decades. We’ve only recently begun to realise that this is at least in part due to molecular epigenetic effects, which result in impaired developmental programming and life-long defects in gene expression and cellular function.
As already highlighted, there are extremely powerful ethical and logistical reasons why humans are a difficult species to use experimentally. Tragically, historical events, terrible at the time, conspire to create human scientific study groups by accident. One of the most famous examples of this is the Dutch Hunger Winter, which was mentioned in the Introduction.
This was a period of terrible hardship and near-starvation during the Nazi fuel and food blockade of the Netherlands in the last winter of the Second World War. Twenty-two thousand people died and the desperate population ate anything they could find, from tulip bulbs to animal blood. The dreadful privations of the population created a remarkable scientific study population. The Dutch survivors were a well-defined group of individuals all of whom suffered just one period of malnutrition, all of them at exactly the same time.
One of the first aspects to be studied was the effect of the famine on the birthweights of children who had been in the womb during the famine. If a mother was well-fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition for the first three months of the pregnancy only (because the baby was conceived towards the end of this terrible episode), but then was well-fed, she was likely to have a baby with normal body weight. The foetus ‘caught up’ in body weight, because foetuses do most of their growing in the last few months of pregnancy.
But here’s the thing – epidemiologists were able to study these groups of babies for decades and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general population. Even more unexpectedly, the adults whose mothers had been malnourished only early in their pregnancy had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including certain aspects of mental health. If mothers suffered severe malnutrition during the early stages of pregnancy, their children were more likely than usual to develop schizophrenia. This has been found not just in the Dutch Hunger Winter cohort but also in the survivors of the monstrous Great Chinese Famine of 1958 to 1961, in which millions starved to death as a result of Mao Tse Tung’s policies.
Even though these individuals had seemed perfectly healthy at birth, something that had happened during their development in the womb affected them for decades afterwards. And it wasn’t just the fact that something had happened that mattered, it was
when
it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.
when
it happened. Events that take place in the first three months of development, a stage when the foetus is really very small, can affect an individual for the rest of their life.
This is completely consistent with the model of developmental programming, and the epigenetic basis to this. In the early stages of pregnancy, where different cell types are developing, epigenetic proteins are probably vital for stabilising gene expression patterns. But remember that our cells contain thousands of genes, spread over billions of base-pairs, and we have hundreds of epigenetic proteins. Even in normal development there are likely to be slight variations in the expression of some of these proteins, and the precise effects that they have at specific chromosomal regions. A little bit more DNA methylation here, a little bit less there.
The epigenetic machinery reinforces and then maintains particular patterns of modifications, thus creating the levels of gene expression. Consequently, these initial small fluctuations in histone and DNA modifications may eventually become ‘set’ and get transmitted to daughter cells, or be maintained in long-lived cells such as neurons, that can last for decades. Because the epigenome gets ‘stuck’, so too may the patterns of gene expression in certain chromosomal regions. In the short term the consequences of this may be relatively minor. But over decades all these mild abnormalities in gene expression, resulting from a slightly inappropriate set of chromatin modifications, may lead to a gradually increasing functional impairment. Clinically, we don’t recognise this until it passes some invisible threshold and the patient begins to show symptoms.
The epigenetic variation that occurs in developmental programming is at heart a predominantly random process, normally referred to as ‘stochastic’. This stochastic process may account for a significant amount of the variability that develops between the MZ twins who opened this chapter. Random fluctuations in epigenetic modifications during early development lead to nonidentical patterns of gene expression. These become epigenetically set and exaggerated over the years, until eventually the genetically identical twins become phenotypically different, sometimes in the most dramatic of ways. Such a random process, caused by individually minor fluctuations in the expression of epigenetic genes during early development also provides a very good model for understanding how genetically identical
A
vy
/a
mice can end up with different coat colours. This can be caused by randomly varying levels of DNA methylation of the
A
vy
retrotransposon.
A
vy
/a
mice can end up with different coat colours. This can be caused by randomly varying levels of DNA methylation of the
A
vy
retrotransposon.
Such stochastic changes in the epigenome are the likely reason why even in a totally inbred mouse strain, kept under completely standardised conditions, there is variation in body weight. But once a big environmental stimulus is introduced in addition to this stochastic variation, the variability can become even more pronounced.
A major metabolic disturbance during early pregnancy, such as the dramatically decreased availability of food during the Dutch Hunger Winter, would significantly alter the epigenetic processes occurring in the foetal cells. The cells would change metabolically, in an attempt to keep the foetus growing as healthily as possible despite the decreased nutrient supply. The cells would change their gene expression to compensate for the poor nutrition, and the patterns of expression would be set for the future because of epigenetic modifications to the genes. It’s probably no surprise that it was the children whose mothers had been malnourished during the very early stages of pregnancy, when developmental programming is at its peak, who went on to be at higher risk of adult obesity. Their cells had become epigenetically programmed to make the most of limited food supply. This programming remained in place even when the environmental condition that had prompted it – famine – was long over.
Recent studies examining DNA methylation patterns in the Dutch Hunger Winter survivors have shown changes at key genes involved in metabolism. Although a correlation like this doesn’t prove cause-and-effect, the data are consistent with under-nutrition during the early developmental period changing the epigenomic profile of key metabolic genes
7
.
7
.
It’s important to recognise that even in the Dutch Hunger Winter cohort, the effects that we see are not all-or-nothing. Not every individual whose mother had been malnourished early in pregnancy became obese. When scientists studied the population they found an increased
likelihood
of adult obesity. This is again consistent with a model where random epigenetic variability, the genotypes of the individuals and early environmental events, and the responses of the genes and cells to the environment combine in one great big complicated – and as yet not easily decipherable – equation.
likelihood
of adult obesity. This is again consistent with a model where random epigenetic variability, the genotypes of the individuals and early environmental events, and the responses of the genes and cells to the environment combine in one great big complicated – and as yet not easily decipherable – equation.
Severe malnutrition is not the only factor that has effects on a foetus that can last a lifetime. Excessive alcohol consumption during pregnancy is a leading preventable cause of birth defects and mental retardation (foetal alcohol syndrome) in the Western world
8
. Emma Whitelaw used the
agouti
mouse to investigate if alcohol can alter the epigenetic modifications in a mouse model of foetal alcohol syndrome. As we have seen, expression of the
A
vy
gene is epigenetically controlled via DNA methylation of a retrotransposon. Any stimulus that alters DNA methylation of the retrotransposon would change expression of the
A
vy
gene. This would affect the colour of the fur. In this model, fur colour becomes a ‘read-out’ that indicates changes in epigenetic modifications.
8
. Emma Whitelaw used the
agouti
mouse to investigate if alcohol can alter the epigenetic modifications in a mouse model of foetal alcohol syndrome. As we have seen, expression of the
A
vy
gene is epigenetically controlled via DNA methylation of a retrotransposon. Any stimulus that alters DNA methylation of the retrotransposon would change expression of the
A
vy
gene. This would affect the colour of the fur. In this model, fur colour becomes a ‘read-out’ that indicates changes in epigenetic modifications.
Pregnant mice were given free access to alcohol. The coat colour in the pups from the alcohol-drinking mothers was compared with the coat colour of the pups from pregnant mice that didn’t have access to booze. The distribution of coat colours was different between the two groups. So were the levels of DNA methylation of the retrotransposon, as predicted. This showed that the alcohol had led to a change in the epigenetic modifications in the mice. Disruption of epigenetic developmental programming may lead to at least some of the debilitating and lifelong symptoms of foetal alcohol syndrome in children of mothers who over-use alcohol during pregnancy.
Bisphenol A is a compound used in the manufacture of poly-carbonate plastics. Feeding bisphenol A to
agouti
mice results in a change in the distribution of coat colour, suggesting this chemical has effects on developmental programming through epigenetic mechanisms. In 2011 the European Union outlawed bisphenol A in drinking bottles for babies.
agouti
mice results in a change in the distribution of coat colour, suggesting this chemical has effects on developmental programming through epigenetic mechanisms. In 2011 the European Union outlawed bisphenol A in drinking bottles for babies.
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